- substituted -



Patented June 16, 1953 4 SUBSTITUTED-"2 (TERTIARY AMINO- ALKOXYl-BENZONITRILES AND THEIR PREPARATION Raymond j'o. Clinton, North Gr'eenb'ush, and Stanley CI-Iiaskowski, Menands, N. Y., assignors to Sterling Drug-Inc New York, N.' Y.,":a corpora'tion of Delaware No Drawing. Application September- 5, 195 1, Serial No. 245,243

1 This invention relates to -4-"substltuted-2- 1'7 Claims. (Cl. 260294.-7)

(tertiaryaminoalkoxy) --benzonitriles "and to their preparation.-

The "compounds of our inventionhav'e the general *formula where Z .is .nitro, amino, lower alkylamino or lower. :hydroxyalkylamino, X is .a lower v-alkylene radical .and .NRRI is aa tertiary-amino radical. These n'itriles, especially the compounds where Z is N02, have utility as intermediates, for instance, .in the preparation of :the corresponding quaternarysalts which are .disclosed and claimed in our copending application Serial No. 245,247, filed September -5,, 1951. In addition, some of these 4 substituted-Z- (tertiary-aminoalkoxy) benzonitriles have useful pharmacological properties, such as, local anesthetic activity and analgesic activity. V I

In the above general formula, the lower alkylene radical designated as X has preferably two to four carbon atoms and has its twofree valence bonds on different carbon atoms. Thus, X includes such examples as and the like. above as NRRJ, comprehends dialkylamino radi- The tertiary-amino radical shown cals where "R, and R1 arelower alkyl "groups,

lower alkylamino, the'lower alkyl radical, desig-' z-amyr n-hexyl, and the like.

. I12 nated as m qneremaeiow, mm; preferably one to six carbon atbms, ihcltfding 1 methylpetnylgn-mony, martyr isobiityh n III H R;

p x-man,

diethylam'inoethyl halide, preferably the emoride, to yield 4-nitro- 2 (2=diethy1aininoethbiiy) benzonitrile, reducing this 4-nitro compound to yield the corresponding 4-amino-2-(2-diethylaminoethoxy)benzonitrile and then alkylating this 4-amin0 compound to produce 4- n-butylamino-2- -diethylaminoethoxy) benzonitrile.

Step I is carried out preferably using 4-nitro- Z-hydroxybenzonitrile in the form of a metal salt thereof, preferably an alkali metal salt, with the tertiary-aminoalkyl halide. Alternatively, Step I can be carried out using 4-nitro-2-hydroxybenzonitrile itself, however, with a resulting decrease in yield of the 4-nitro-2-(tertiaryaminoalkoxy)benzonitrile. The reduction Step II is carriedout either by chemical methods or by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. In practicing our invention, we preferably used iron and hydrochlric acid.

Catalysts suitable when catalytic hydrogenation is employed include Raney nickel, platinum, palladium or other catalysts generally effective tocatalyze hydrogenation ofnitro groups to amino groups. 1

. The alkyiation of the 4-amino-2-(tertiaryaminoalkoxy)benzonitriles (D) to produce the related .l-alkylaminoor 4-hydroxyalkylamino-' nitriles (Step-III) where R2 has-from three to six carbon atoms is preferably carried out by reductively alkylating the l-amino compound with an alkanal or a hydroxyalkanal. Thus, this preferred-method ofalkylating the -amino nitriles (D) is by treating a mixture of a 4 -amino-2- (tertiary-aminoalkoxy)-benzonitrile and an alkanal ,or hydroxyalkanal, having from three to six carbon atoms, ina reducing medium. This reduction can be carried out either by chemical methods or by catalytic hydrogenation. Illustrative of this reduction step is the formation of 4-n-amy1amino-2- [3-(1-piperidyl) propoxyl benzonitrile or 4-(5-hydroxyamylamino)-2-[3- (l-piperidyl)propoxylbenzonitrile by treating a bromide, n-propyl bromide, isobutyl iodide,-2-

hydroxyethyl bromide, 4-hydroxybutyl chloride, and the like,,in.the presence of a hydrogen halide acceptor, e; g., sodiumbicarbonate, potassium carbonate, ctc. Thus, such treatment of 4- amino 2- (3 diethylaminopropoxy)benzonitrile with metehyl iodide, ethyl bromide or 2-' hydroxyethyl bromide yields, respectively, 4-

methylamino 2 (3 diethylaminopropoxyb benzonitrile, 4-ethy1amine-2-(3-diethylaminopropoxy) benzonitrile or 4- (Z-hydroxyethyl) amino 2 (3 diethylaminopropoxy)benzonitrile. Yields of the resulting l-alklaminoand l-hydrOXyalkyIaminO-Z-(tertiary-aminoalkoxy) benzonitriles obtained by this method are lower than those obtained-by the foregoing described, reductive alkylation procedure due to quaternary salt formation.

' zenesulfonate, dihaloalkane, etc.

-, ganic or inorganic acids.

Step I can also be carried out stepwise, that is, by first haloalklating 4-nitro-2-hydroxybenzonitrile (A) to form a 4-nitro-2-(haloalkoxy)benzonitrile which is then treated with a secondary amine having the formula HNRR1. The first step can be accomplished by treating -nitro-2-hydroxybenzonitrile or a metal salt thereof with a haloalklating agent such as a haloalkyl paratoluenesulfonate, haloalkyl ben- As illustrations of this stepwise procedure, 4-nitro-2-hydroxybenzonitrile is haloalkylated by treating its sodium salt with 2-chloroethyl para-toluenefsulfonate to form 4-nitro-2-(2-chloroethoxy)- benzonitrile which then is treated with diethylamine or piperidine to form 4-nit1o-2-(2-diethylaminoethoxy) benzonitrile or 4-nitro-2-[2- 1 -piperidyl) -ethoxy] benzonitrile, respectively.

Another method of preparing the 4-nitro-2- (tertiary-aminoalkoxy)benzonitriles (C) of our invention except those where the tertiary-amino radical NRR1 is dimethylamino is afforded by a sued January 20, 1953. The tertiary-amino:

alkyl 6-nitrobenzisoXazole-3-carboxylates are also disclosed and are claimed in our copending application Serial No. 245,245, filed, September 5, 1951, now United States Patent 2,626,260, issued January 20, 1953. v

The 4-substituted-2- (tertiary-aminoalkoxy) benzonitriles of our invention are therapeutical- 1 active or useful as intermediates whether em ployed in the form of their'free bases or in the form of their salts with relatively non-toxic or- In practicing our invention, we found it convenient to isolate our compounds in the form of their hydrochlorides or phosphates. However, other acid addition salts are within the scope of our invention. Such salts include the hydrobromides, sulfates, ci-

trates, sulfamates, tartrates, succinates, acetates, benzoates, oleates, and the like.

Specific embodiments of our invention are i1" lustrated by the following examples.

2 (1) -nitro-Z-(tertiary-aminoalkoxy) benzo-a m'trz'les Preparation of the 4-nltro-2-(tertiary-amino alkoxy)benzonitriles of our invention is illustrated by the following alternative procedures, all of which involve alkylation of 4-nitro-2-hydroxybenzonitrile or a metal saltthereof with a tertiary-aminoalkyl halide for, stepwise, with a haloalkylating agent such as a haloalkyl paratoluenesulfonate to produce a 4-nitro-2-(haloalkoxy)benzonitrile which is then treated with a secondary amine to form the desired 4-l'litTO-r 2- (tertiary-aminoalkoxy) benzonitriles.

Procedure (a) .To a warm solution of 82.0 g. of 4-nitro-2-hydroXybenzo-nitrile and 1000 ml. of absolute ethanol was added a solution of 11.5 g. of sodium in 500 ml. of absolute ethanol. To the resulting deep carmine-colored solution was added 74.5 g. of 2- diethylaminoethyl chloride (the distilled free base can be conveniently rethoroughly with absolute ethanol.

placed by theequivalent amount of .2-diethyla- .minoethyl chloride hydrochloride and an additional equivalent of sodium ethoxide), .the mixture Was refluxed with stirring for five hours, filtered while hot, and the filter-cake was washed The combined filtrates were --evaporated in vacuo, the residue was dissolved in ethyl acetate'and the solution was filtered. To the filtrate was added anexcess of 20% ethereal hydrogen chloride solution. The resulting precipitate of 4-nitro-2- (2 diethylaminoethoxy.) benzonitrile hydrochloride was collected and recrystallized several times from absolute ethanol-ether. The yield of purifiedmaterial was 112.0 g. (85%), ..P. 193.2-l94.6 C. (cor).

Amzl.Calcd..for JCmI-IuNsOa-HCI: Cl, 11.83; N ,14;02. "Found: C1. 11.75; N ,.14.02.

ND stands for total nitrogen as determined by the Dumas method.

Conversion of the above hydrochloride into the corresponding base was accomplished by dissolving the hydrochloride in water and precipitating the base by addition of solid potassium carbonate. The precipitated base, 4-nitro-2-(2- diethylaminoethoxy)benzonitrile, which was obtained in 97% yield from the hydrochloride, crystallized from n-heptane in large, pale yellow leaflets, mp. 104.5-1055 C. (con).

AnlaZr-Calcd. for C13H17N303I C, 59.30; H, 6.51; NBA, 5.32; NNO2, 5.32. Found: C, 59.43; H, 6.58; NBA, 528; NNo 5.00.

N stands for basic'amino nitrogen as determined by on. N stands for nitro nitrogen as determined by titration with standard titanous chloride in glacial acetic acid solution.

When a 3-(tertiary-amino) propyl chloride was substituted in the above procedure for .2-diethylaminoethyl chloride, there was added 6 g. of "sodium iodide per mole of chloride base and'the refluxed period was increased totwenty hours. The yields of purifiedl-nitro-2-[3-(tertiaryamino) propoxylbenzonitriles, which are given below in Table I, varied from 65 to 90%.

The substitution of Z-dimethylaminoethyl chloride for Z-diethylamin'oethyl chloride in the above procedure gavenone of the desired :product. Instead, cyclization of the .,.2-.dimethylaminoethyl chloride occurred exclusively, .and a high yield of 1,1,4.4tetramethylpiperazinium di- (Z-cyano-5-nitrophenolate) was isolatedfm. p. 2124-2133 C. (co-r.) with decomposition. However, Z-dimethylaminoethyl chloride can be used successfully in this alkylation by using a nonpolar solvent, such as benzene or toluene, in place of the polar solvent, ethanol, as described below in Procedure (5).

1-Dimethylamino-2-propyl chloride "gave a mixture of products indicating that partial The lrpronoxylbenzonitrile .(F) vor .4enitroe2-(3edimethylammovz propoxy)benzonitrile G) having the Sfollowing respective .formulas Anal'r-eCalcd .for .C12H15N30'32 Nno 5.62; NBA, 5.62. .FQuhdtNuo 5.60; NBA, 5.58. v The hydrochloride of this basic nitrile (F or G) ,formed pale yellow prisms from ethanol, m.p. 2121-2127" C. (con). .AnaZ.C-alcd. for -.C12H15N303'HC12 NN02,'4.90 01.12.41. Found:NNo 5.04; Cl,12.39. V

.The vetlt yllacetate insoluble red precipitate, obtained above, was recrystallized several times from absolute ethanol-n-hexane or from isopropanol containing water. The compound crystallized in clusters of slender red needles from the former solvent combination and in large thin rectangular orange plates from the latter solvent. The orange form. (a. hydrate) was converted into the anhydrous red form on heating at 100 C. Quantitative degradation *experiments'indicated that this compound was 1,1,2,4,4,5-hexamethylpiperazinium di-(Z-cyano 5-nitrophenolate) Procedure (1)) .--A mixture of 82.0 g. of 4-nitro- Z-hydroxybenzonitrile, 70.3 g. of powdered anhydrous potassium carbonate and 2500 m1. of

toluenewas'refluxed with stirring under a continuous water separator for three hours. During this period 4.5 ml. of water was collected. The continuous water separator. was removed and there Was added 54.0 g. of Z-dimethylaminoethyl chloride. The mixture was refluxed with stirring for sixteen hours, treated with an additional 10.8.v g. of 2-ldimethylaminoethyl chloride and refluxed withstirring for an additional eight hours.

The mixture was filtered while hot, the insoluble moved by filtration. The ethyl acetate solution was decolorized and treated with-an excess of ethereal hydrogen chloride. The resulting crys ta lline hydrochloride was collectedwashed with ethyl acetate and reconverted to. the base; the

materialwas washed with hot toluene, and the combined filtrates were decolorized and evaporated in vacuo. The resulting'solidwas recrystallized several timesfrom n-heptane, yielding 77.1 g. (65%) of purified 4-nitro-2-(2-dimethylaminoethoxy)benzonitrile, m. p. 83.1-84.0 C. (con).

Anal.Calcd. fOr C11H13N3O32 NBA, 5.95; Nivo 5.95. Found: NBA, 5.98; NNO2, 6.25.

4 Nitro 2 (2 dimenthylaminoethoxy) benzonitrile in the form of its hydrochloride salt melts at 229.5-230.3 C. (cor.).

Anal.Cal cd..for CiiHisNaOs; Cl, 13.05 NNOZ, 5.16. Found: C1, 12.79; NNQ 5.28.

' Procedure (0) .A mixture of 82.0 g'. of 4-nitro- Z-hydroxybenzonitrile, 76.0 g. of powdered anhydrous potassium carbonate, 141.0 g. of 2-chloroethyl para-toluenesulfonate and 1350' ml. of meta-xylene was refluxed with stirring under a continuous water separator for seventy-eight hours. The mixture wasfiltered while hot and the insoluble material was washed thoroughly withhot toluene. The combined filtrates were concentrated to dryness in vacuoand the residual solid :was recrystallized from absolute ethanol. Therewasthus obtained a 67.5% yield of purified 4'nitro-.2-(2-chloroethoxy)benzonitrile, as slenqiler, )pale yellow needles, m. p. 1274-1285 C. cor.

"15.65. Found: Nno 6.30; 01, 15.30.

The reaction of 4-nitro-2-(2-chloroethoxy)- benzonitrile with a secondary amine in aqueousdrous isopropanol was refluxed for one hour. During initial dissolution of the acid in the alcohol-amine mixture an orange color developed and carbon dioxide was vigorously evolved. On working up there was obtained 5.2 g. (58% yield) of purified 4-nitro-2- (Z-diethylaminoethoxy) benzonitrile hydrochloride, m. p. and mixed m. p. 1932-1946 C. (con).

AnaL-Calc'd. for C13H17N303'HC13 C, 52.09; H, 6.05; N 14.02; NNo 4.67; Cl, 11.83. Found: C, 52.29; H, 5.91; N 14.07; NN02, 4.55; 01, 11.79.

The foregoing process as illustrated by Procedure (e) is disclosed and claimed in our copending application Serial Number 245,250, filed September 5, 1951, now United States Patent 2,626,261, issued January 20, 1953. r

Additional 4-nitro-2-(tertiary-aminoalkoxy) benzonitr-iles prepared according to the above de- Procedure (e) .A solution of 6.2 g. of G-nitro- 20 bed procedures are iven in Table I.

V v 7 TABLE I O (OHI)|\ RR1 I V Analyses, Percent c 11. NRR g Formula NBA NM,

' Oaled. Found Oalcd Found 3 N(C2H5)2 53. 6-55. 0 OuHmNaOa 5.05 5. O4 5. O5 92 2 NfCaHm 118. 1-119. 2 CuHuNaOz 5. 09 5. 07 5. 09 5. O5 2 N 0511 133. 4-136. 2 G15H1DN303 "4. 48 4. 82 14. 52 14. 24 2 1JC7H 132. 9-133. 8 CmHmNaOg 4. 62 4. 65 4. 62 4. 76 3 NCgHm 102. 2-102. 8 CnsHmNaOa 4.84 4. 87 4. 84 4. 80 3 NOfiHfl 3. 5-93. 5 CmHnNaOa 4. 62 4. 64 4. 62 4. 2 NC H3O 126. 5-127. 5 C13Hi5NaO4 5. 05 5. 07 V 5. 05 5.05 3 NC HaO' 110. 0-111. 5 CuHnNaO; 4. 81 4. 82 4. 81 4.

e N C sHm l-piperidyl benzisoxazole-3-carboxylic acid and 5.4 g. of 2- diethylaminoethyl chloride in 100 ml. of anhy- Hydrochloride addition salts of the compounds of Table I' are given in Table II.

TABLE II -0(OH:)NRR1-HG1 Analyses, Percent 1 M. I Min. i 0 Formula 01 NN 0,

Salad. Found Oalcd. Found 1 3 N(C2Hb)z 2l0.2210.9 C14H19N303.HC1 11. 30 11. 3O 4 46 2 NO5Hw= a C14H11NaO;.HO1 11.37 11. 33 4: 49 2 NCQHH" 192.7-193.7 C 5H191N3O3.HC1 10. 88 10. 80 12. 90 d 13 04 2 NCiHn 214.6215.3 C1nH11NaOa.HC1 10. 43 10. 3O 4. 12 4. 26 E3 NC5H 0" 194.0194.9 C15HWN9O3.HC1 10. 88 10. 83 4. 30 4. 30

. NC Hfl 187.1-188-0 CmHg1N303.HO1 1U. 43 10- 27 d 12. 37 d 12. 12' 2 NCAHBO 214.6215.5 01741115151304.1101 11. 3O 11. 31 4. 47 4. 35 3 LTCHH O 21511-2158 C14H17NaO4.HC1 10. 82 10. I 4. 27 4. 19

6 Total nitrogen by the Dumas method J NC H14=2,6-dimethyl-1-piperidy1.

1 piperidyl)ethoxylbenzonitrile; 4.- nitro 2 [3 (2 methyl 1 pyrrolidyl)propoxylbenzonitrile; and the like.

(2) 14-a1nino-2 (tertiary-animoalkory)- beneom'trz'les These compounds were L prepared, by red uction of the corresponding a-nitro 2-(tertiary-aminoalkoxy)benzonitriles, as described hereinabove.

Illustrative of this reduction are the following examples.

To a hot vigorously stirred mixture of 64.5 g.-

of powdered iron, 1 ml. of concentrated hydrochloric acid and 250 ml. of 50% aqueous ethanol was added slowly over a period of'about ten minutes 57.4 g. of l-nitro-2-(2-diethylaminoethoxy) benzonitrile hydrochloride. The resultant mixture was heated with stirring for another thirty minutes, after which time an excess of solid sodium bicarbonate was carefully added. The mixture was stirred for an additional ten minutes and then filtered through a filter aid which was subsequently washed with hot ethanol. The combined filtrate and washings were concentrated by distilling in vacuo, thereby yielding, as an oil, the product, 4-amino-2- (2-diethylaminoethoxy) benzonitrile.

Alternatively, the foregoing preparation can be carried out using 4-nitro-2-(Z-diethylaminoethoxy)benzonitrile in place of 4-nitro-2-(2-diethylaminoethoxy) benzonitrile hydrochloride.

The phosphate salt of the above 4-amino nitrile was prepared by dissolving about 12 g. of l-amino-2- (2-diethylaminoethoxy) benzonitrile in 100 ml. of hot isopropanol, addingto this solution a Alternatively, the dihydrochloride salt was prepared by treating a solution of 20 g. of i -amino nitrile in 300 ml. of isopropanol with. an excess of anhydrous ether -containing120% by weightof anhydrous hydrogen chloride and diluting the mixture with ether. The thicjk,pale yellow oil that precipitated was separated byv decanting the solvent mixture and wastaken up in 400 m1'. of boiling isopropanol and precipitated by the addihydrogen chloride is added as above.

iowin'ggenrn prparatiofi f Ten grains; of me 4'-nitro-2- (tertiary-aminoalkoxy) benzo n'itrile in 150 m'lxof ethanol hydrogenated usin'gf so bs. pressure of hydrogen at'25f CI; in the presence a of e c1k r he r id; e89: thrinic reaction, the catalyst is" filtered'offand the filtrate evaporated to dryness. The resulting residueis dissolved in ethyl acetate and ethereal Alterna tively, other catalysts can be employed as exemplified in the following use of platinum: Fif

teen grams 0f a 4-nitro-2-(tertiary-aminoal-. koxy)benzonitrile in' 150. ml. ;of ethanol is reduced at 25 lbs. pressure of hydrogen at 25? G.

in the presence of, 200 mg. of platinum oxide monohydrate andfrrnl. of concentrated hydrot'ion; tliecatalyst is. filtered;off and the filtrate distilled in vacuo to remove the alcohol. ""I'he residue is takenupinzwater and potassium carbonate is added to theresulting solution to liberate the 4-amino-2-. (tertiary-aminoalkoxy) benzonitrile, which is extracted with 'ethyl acetate.

The ethyl acetate extract is dried and treated.

chloride, 80 g. of .powderediron, 1 ml. of concentrated hydrochloric acid, 300;ml,.of ethanol and 50 .ml. of water, there w'as'obtained as the product, 4-amino-2 [2- j (4.-morpholiny1) ethoxyl -benzonitrile, which recrystallized from" benzene as rosettes of long fiat whiteneedles, M. P. 130.6-

132.8? C. (cor.) [dried at 80 C. in a vacuum oven] for six hours]. A

AnaL-Calcd. for CisI-InNsOz: N 17.00. FoundzN 17.09. I f.

he preparation of this 4-amino nitrile in the form of its monohydrochlorid'e'salt was accomp isljledasfqllowsf- Toasolution of 5g. .of 4-amino-2-[2 -(4 H solved in lQQ ml .of warm ethyl acetate was added an excess of ethereal hydrogen chloride, thereby yielding an amorphous white precipitate. The precipitate was filtered, washed well with ethyl acetate and recrystallized by dissolving it in a minimum quantity of hot absolute ethanol and then. adding tothis hotsolution about two volumes of ethyl acetate. The precipitated dihydrochloride was collected washed with ethyl acetate and dissolvedin .100 ml. of hot ethanol. To this solution was added 6 g. of 4-amino-2-[2-(4-morpholinyl)ethoxylbenzonitrile and the solution tion of 300 ml. of ethyl acetatefifollowed by cooling. The product was filtered and recrystallized several times from isopropanol-ethyl acetate. There was thus obtained 4-amino-2-(2-diethylaminoethoxy)ben'zonitrile dihydrochloride.

The above reduction of the 4-nitro-2-(t ertiary--' aminoalkoxy) benzonitriles to yield the fcorresponding l-amino nitrile's can be oarrie'dout by catalytic hydrogenation'as illustrated by the fol was heateduntil dissolution ofthe4-amino nitrile was complete. The'rsulting solution was cooled, and then diluted to about 1 liter with 1:1. 7 ethyl acetate-.ethen. ;.The gummy material" that separated was boiled with absolute ethanol and the hotmixture treated Wit hJZ volumes of ethyl e e; Q Q i there separated a crystalliri e precip at The compouiidiobtai'ned above y tsetse-1.

sodiumsa'lt'of 4 -nitro z hydroxyberizoriitrile with v v v whichfwas c lle'cted and recrystal lized once romjethaznolethyl. acetate and once. from absolute ethanol, therebyyielding, as large 11'- 1-dimethylamino-2-propy1 chloride, on treatmentwith a reducing agent according to the foregoing procedures yields a compound that is either 1 amino 2 -(2-dimethylamino-1-propoxy)benzonitri le (H) or 4-amino-2-(3-dimethylamino-2- propoxymenzonitrile (I) having the following respective formulas NH: NH:

Additional 4-amino-2- (tertiary-aminoalkoxy) benzonitriles prepared according to the above procedures are given in Table III.

zonitrile; 4 Q amino 2 [2 (2,5 diinethyl pyrrolidyl) ethoxylbenzonitrile; i amino 2-" (4-dimethylaminobutoxy) benzonitrile; 4-amino- 2 [2 (di n butylamino) ethoxylbenzo 5 nitrile; 4 amino a 2 [3.- (4 methyl 1 piperidyl) propoxyJbenzonitrile; 4 amino 2- [2' (3 ethyl 1 -.piperidyl) ethoxy] benzonitrile; 4 amino 2 3 (2 methyl 1 pyrrolidyl) propoxylbenzonitrile; and the like.

(3) 4-alkylaminoand 4-hydromyalkylamino- 2- (tertiary-aminoallcozcy) benzom'trzles These compounds were produced by alkylation of the corresponding 4 amino 2 (tertiary-aminoalkoxy) benzonitriles described above. This alkylation was run preferably by reductive alkylation procedures as illustrated in the following examples.

4 n Butylamino 2 (2 diethylamino- 6 Basic amino nitrogen as determined by titration with perchloric acid in glacial acetic acid solution.

= NO4H O =4-morpholinyi.

- Phosphoric acid addition salts of the compounds of Table III are given in Table IV.

ethoxy)benzonitrile was prepared as follows: To a hot stirred mixture of g. of 4-amino- TABLE IV ()(CH2),.NRR -H!P 04 Analyses O n NRR; f Formula 7 HzPO; ND

Calcd. Found Oalcd. Found 3 N(C;H5)z 237. 5-238. 2 CnHmNaOQHsPO; 28. 39 28. 52 12. 17 11. 92 2 NCaHm 5 198. 0-198. 7 CuHuNaO. HsPOi 28. 28. 12. 24 12. 05 2 NCaHm b 192. 5-194. 0 CiaHnNsO. HaPO4 27. 43 27. 50 11. 76 11. 56 2 NCzHu 193. 5-195. 5 CmHzaNaQHaPOi 26. 40 26. l0 11. 31 11. 19 3 NCsHw 202. 1-203. 3 CnHmNaQHsPO; 27. 43 27. 83 11. 76 ll. 60 3 NGuHu b 214. 8-216. 7 C1oH23NSOJ1sP04 26. 40 26. 40 11. 31 11. 20 3 NCiHaO 190. 5492. 2 CuHmNaOLHzPO4 27. 28 27. 52 11. 69 11. 55

a NCtH1u=1piperidy1.

b NCsHu=2-methyl-1-piperidyl.

v N0 H=2,6-din1ethyl-l-piperidyl. d NCAHBO =4-morpholinyl.

Additional 1 i-amino-2-(tertiary-aminoalkoxy) benzonitriles which can beprepared according to the foregoing procedures include the following:

4-amino-2- [3- (l-pyrrolidyl) propoxylben- 7 2-(2-diethy1aminoethoxy) benzonitrile, 22.5 g. of zinc dust, 21.2 g. of glacial acetic acid and ml. of dry benzene was added 7.5 g. of n-butanal (n-butyraldehycle) dissolved in 25 ml. of dry egezaaee "13 benzene over a fifteen minute period. Afterthe mixture had been stirred for one hour, an additional 1 ml. of n-butanal was added and stirring continued for an additional fifteen minutes.

The zinc acetate was filtered oil and washed with hot dilute acetic acid and benzene. The cooled filtrate was made basic to litmus with concentrated ammonium hydroxide, the benzene layer was separated and the aqueous solution was extracted three times with benzene. After the combined benzene layer and extracts had been dried over anhydrous potassium carbonate, the benzene was removed by distilling invacuo, yielding, as a mobile yellow oil, 4-n-butyl-amino- 2- (2-diethylaminoethoxy) benzonitrile.

This oily product was converted into its monohydrochloride salt as follows: It was dissolved in isopropanol and the resulting solution was treated with an excess ofethereal hydrogen chloride, whereupon a precipitate readily formed. The precipitate was collected, washed with cold isopropanol and recrystallized from absolute ethanol-ethyl acetate. There was thus obtained, as cottony white needles, 4-n-butyla'mino-2- (2- diethylaminoethoxy) 1 ben'zonitril'e' monohydrochloride, M. P. 210.2-211.0 C. (corp) [dried at 80 C. in vacuo].

AnaZ.-Calcd. for C1'1H2'INsQ'I-IC1: C, 62167; H, 8.36; N 1290; C1, 10.90. Found: C, 62.72; H. 8.47; N 12.95; Cl, 10.76.

When the above procedure is followed but using 4-hydroxybutanal or 5-hydroxypentanal in place of n-butanal, theresulting products are 4 (4 hydroxybutylamino) 2 (2 diethylaminoethoxy)benzonitrile and 4 (5 hydroxyamylamino) 2 (2 diethylaminoethoxy)benzonitrile, respectively.

When the above procedure is followed but 7 OCHaCHN(CHs)1 l 5 Ha ON 4 n Butylamino 2 [2 (2 methyl 1- piperidyl)ethoxylbenzonitrile was prepared following the above procedure but using 15.0 g. of 4 amino 2 [2 (2 methyl 1 piperidyl) ethoxy'lbenzonitrile, 15.2 g. of'zincd'ust',.14.3 g. of glacial acetic acid, 150 ml. of dry benzene and 5.0 g. of n-butanal. Theproduct, 4-n-butylamino 2 [2 (2 methyl 1 piperidyl) ethoxylbenzonitrile, was obtained as a thick, viscous, pale orange oil. The phosphate salt of this product was prepared by dissolving about 14 g. of the oil in 100 ml. of hot ethyl acetate and treating the solution with a solution of 6.5 g. of 85% phosphoric acidin 25 m1. of acetone. The phosphate precipitated as a thick, orangeyellow oil. Ether was added to the mixture which was then chilled. The supernatant-liquid was separated'from the oil by decantationand the oil was taken up in 100 ml. of acetone, where:- upon the phosphate. salt, crystallized. To. this mixture was added 100 ml. of ethyl acetate-and the resulting mixture was chilled. The solid product that separated: was recrystallized. by dissolving it in-about 100 ml. of'water,.filtering and diluting the filtrate to a. volume of about 450 ml. with absolute ethanol- There was thus obtained, after drying at: 100 Cpand 0.01.mm. for four hours, 4-n-butylamino-2 -[2 (2-methy1:- I-piperidyl) ethoxyl'benzonitrile phosphate, m. p. 194.4-1953" C. (cor.).

AnaZ.-Calcd. for C19H29N3OL'H3PO4Z Nb, 10.16,; HzPOz, 23.17.. Found: N 10.11; H3PO4, 23.28. When the above. procedure; is followed: but using; in place of 4-amino.--2-;[.2-(ZAmethyl-lpiperidyl)eth'oxylbenzonitrile, 4. amino 2:- [3--'.'1 piperidylypropoxylbenzonitrile, 4- ami+ no 2 [2 (2,6'I-dimethyl 1 piperidyhethoxylbenzonitrile. ora4 amino -2. [2. (4+ morpholinyl)ethoxylbenzonitrile, there. obtained, in the. form of: their phosphates, 4-nbutylamino 2 [3 (1 piperidyhpropoxyl benzonitrile, 4 n butylamino 2 [2 (2,6-

dimethyl- 1 piperidyl)ethoxylbenzonitrile or 4 n butylamino 2 [2- (4 morpholinyl) ethoxyll-benzonitrile, respectively.

' 4 -n-Amylamino-2- [2- (Z-methyl-l-piperidyl) ethoxylbenzonitrile was obtained, as-a viscous orange-yellow oil, when the above procedure was ,followed but using 1 00 g. of 4-amino-2- [-2 (2 methyl -1-piperidyl) ethoxy'l'benzonitrile,

10.1 g. of zinc dust,-9.5 g. of glacial. acetic acid, 4.0 g; of n-pentanal (n-valeraldehyde) and 100 ml. of dry benzene. Thephosphate of this compound was prepared by dissolving about 11.7 g. of 4-n-amylamino-2-[2 (2-methyl-1-piperidyl-)'- ethoxylbenzonitrile in- 150 ml. of acetone and adding to the resulting solution a solution of 4 g. of phosphoric acid in acetone. The resulting mixture was diluted with ml. of acetone and 100 ml. of ethyl acetate, and chilled in ice, whereupon there separated a white crystalline precipitate. Thisprecipitate was recrystallized by dissolving it 250 ml. of boiling ethanol, filtering the solution and adding to the filtrate ml. of hot isopropanol. This recrystallization was repeated. There was thusobtained,. afterdryingfor. fourhoursat 100 C. and 0.01 mm., 4:--n'-a mylamino-2-[2-(2-methy1-1- piperidyl)ethoxylbenzonitrile phosphate, M. P. 178.0-179.5 C. (cor.).

AnaZ.-Calcd. for C20H31N3Q H3PO4: N 9.83; H3PO4, 22.93. Found: N 9.90; H3PO4, 22.58.

Alternatively, the foregoing reductive a1ky1ations can be carriedout using, in place of zinc dust and glacial acetic acid, hydrogen under pressure in the presence of a hydrogenation catalyst such as platinum.

Other 4-alkylamino-or 4-hydroxyalkylamino- 2 '(tertiary aminoalkoxy)benzonitriles which can 4- isobutylamino-Z ['2-' (-3-ethyl-I-piperidyl) ethoxyl benzonitrile; 4 n'-hexy1amino-2- [3 (2- enemas i methyl l-pvrrolid'y'l)propoxylbenzonitrile; and the like. 7

Alternatively, the lealkylaminoand l-hydroxyalkylamino 2- (tertiary-aminoalkoxy) ben= zonitriles of our invention can be prepared by direct alkylation of the corresponding 4-amino compounds. This mode of alkylation is illustrated by heating 4-amino-2-(2-diethylaminoethoxy benzonitrile with methyl, iodide, ethyl bromide, Z-hydroxyethyl bromide, n-propyl iodide, n-butyl bromide or E-hydroxypentyl chloride in the presence of a hydrogen halide acceptor such as potassium carbonate to yield, respectively, 4-methylamino-2-(Z-diethylamino- 'ethoxy) benzonitrile; .4-ethylamino-2- (Z-diethylaminoethoxy) benzonitrile, 4 n-propylamino-2- (2 diethylaminoethoxy)benzonitrile, 4 (2-hydroxyethylamino) 2 (2 -diethylaminoethoxy) benzonitrile, 4-n-buty1amino-2-(Z-diethylaminoethoxy) benzonitrile or 4- (5-hydroxyamylamino) -2- (Z-diethylaminoethoxy) benzonitrile.

We claim:

1. A compound having the formula where Z is a member of the group consisting of nitro, amino, lower alkylamino and lower hydroxyalkylamino, X is a lower alkylene radical whose two free valence bonds are on different carbon atoms and NRR1 is a member of the group consisting of lower dialkylamino, l-piperidyl. .(lower alkylated) -l-piperidyl, l-pyrrolidyl, (lower alkylated) -1-pyrr0lidyl and 4-morpholinyl.

2. A compound having the formula O--XN (lower alkyl):

where X is a lower alkylene radical whose two free valence bonds are on diiferent carbon atoms.

3. A compound having the formula DIIHI I where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms a NEE; is a lrmp ri l d al.

5. A compound having the formula where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms and NRR1 is a (lower alkylated)-l-pipericlyl radical.

6. A compound having the formula where, X is a lower alkylene radical whose two free valence bonds are on different carbon atoms and NRR1 is a Z-methyl-l-piperidyl radical.

7. A process for the preparation of a compound having the formula where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms and NRR1 is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower a1kylated) -1-piperidyl, l-pyrrolidyl, (lower a1kylated) -l-pyrrolidyl and 4-morpholinyl, which comprises treating the corresponding 4-nitro-2- (tertiary-aminoalkoxy) benzonitrile with a reducing agent.

8. A process for the preparationof a 4-amino- 2' (dialkylaminoalkoxy) benzonitrile having I the formula O-X-N (lower alkyl);

O- X-N(C2H5)i where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms, wh ch comprises treating the corresponding 4- 1 Z nitro-2-(diethylaminoalkoxy)benzonitrile with a reducing agent.

10. A process for the preparation of a -amino- Z-(tertiary-aminoalkoxy) benzonitrile having the formula OX'NRR1 I CN Where X is a lower alkylene radical whose two free valence bonds are on difierent carbon atoms and NRR1 is a l-piperidyl radical, which comprises treating the corresponding 4-nitro-2-(ter-' tiary-aminoalkoxy)benzonitrile with a reducing agent.

11. A process for the preparation of a i-amino- Z-(tertiary-aminoalkoxy) ienzonitrile having the formula NHa where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms and NRR1 is a (lower alkylated) -1-piperidyl radical, which comprises treating the corresponding i8 4-nitro-2-(tertiary aminoalkoxy) benzonitrile with a reducing agent. 1

12. A process for the preparation of a a-amino- 2- (tertiary-aminoalkoxy) benzonitrile having the formula 1 benzonitrile.

15. 4- Amino-2-[2 (l-piperidyDethoxylbenzonitrile.

16. 4 Amino-2-[3-(l-piperidyl)propoxylbenzonitrile.

1'7. 4 Amino 2 [2-(2-methy1-1-piperidyl ethoxylbenzonitrile.

RAYMOND O. CLINTON. V STANLEY C. LASKOWSKI No references cited. 

1. A COMPOUND HAVING THE FORMULA 